The present invention relates to bicyclic amide derivatives, to processes for their preparation, and to their use in therapeutic treatments.
Ion channels are transmembrane proteins that regulate the passage of various ions through the membrane. Ion channels are physiologically important, playing essential roles in regulating intracellular levels of various ions and in generating or modulating action potentials in nerve and muscle cells. Passage of ions through ion channels is characterized by selective filtering and by a gating-type mechanism which produces a rapid increase in permeability (Angelides, K. J., et al., J. Biol. Chem., 1981, 258, 11858). Ion channels may be either voltage-gated, implying that current is gated (or regulated) by membrane potential (voltage), or chemically-gated, implying that current is gated primarily by binding of a chemical agent rather than by the membrane potential (Butterworth, J. F., et al., Anesthesiology, 1980, 72, 711). An important characteristic of certain voltage-gated ion channels is inactivation. Soon after opening, these channels close via various mechanisms, forming an inactive channel complex that will not return to its active state until the membrane is repolarized (Miller, C., Science, 1991, 252, 1092).
The ion-conduction pore of these channels is composed of heterotetramers of different, but structurally-related, α-subunits. Each α-subunit consists of an approximately 600-amino-acid polypeptide which possesses six membrane-spanning α-helices (Kolb, 1990; Shi, G., et al., Neuron, 1996, 16, 843). The α-subunits of mammalian voltage-gated potassium channels are currently divided into four related gene-families, based on homology with the corresponding gene families originally derived from work with Drosophila melanogaster. These four groups are the Kv1 (Kv1.1-1.8, the so called Shaker family), Kv2 (Kv2.1-2.2, the Shab family), Kv3 (Kv3.1-3.4, the Shaw family) and Kv4 (Kv4.1-4.1, the Shal family) gene subfamilies (for a review, see Chandy, K. G. and Gutman, G. A., in Handbook of Receptors and Channels: Ligand and Volgate-Gated Ion Channels, CRC Press, pages 1 to 71, 1995 and references cited within.
In some cases, each α-subunit is closely associated with a β-subunit which does not participate in ion conductance directly but can regulate the activity of the channel (for reviews, see: Xu, J. and Li, M., Trends Cardiovasc. Med., 1998, 8, 229; Pongs, O., et al., Ann. N.Y. Acad. Sci., 1999, 868, 344). The known β-subunits have been assigned to three classes, Kvβ1-3, and several splice variants of Kvβ1 have also been described. One well-documented activity of the Kvβ1 subunit is to confer rapid inactivation on the current-conducting α-subunit, which normally displays slow inactivation in the absence of the β-subunit (Rettig, J., et al., Nature, 1994, 369, 289). As in the Drosophila-derived Shaker family, the inactivation conferred by mammalian Kvβ1 involves the N-type “ball-and-chain” mechanism (Zagotta, W. N., et al., Science, 1990, 250, 568; Isacoff, E. Y., et al., Nature, 1991, 353, 86). Thus, in this role Kvβ1 acts as a switch, shutting off the voltage-gated potassium channel once it has performed its function of repolarizing the membrane.
Voltage-gated potassium (KV) channels participate in several cellular processes. In excitable tissues, these ion channels play an essential role in establishing the resting membrane potential and in modulating the frequency and duration of the action potential (Hille, B., Ionic Channels of Excitable Membranes, Sunderland, Mass., 1992). In nonexcitable cells, they are involved in cell volume regulation, hormone secretion, oxygen sensing and cell proliferation (Kolb., H. A., Rev. Physiol. Biochem. Pharmacol., 1990, 115, 51). Thus, Kv channels are key regulators of neuronal excitability and their dysfunction is believed to be associated with a variety of abnormal conditions or diseases.
For example, implications for a role of Kv1.1 in epilepsy come from varied sources (for a review, see Rho, J. M., Dev. Neurosci., 1999, 21, 320). Kv1.1 genes are richly expressed in brain regions which are susceptible to epileptic seizure, such as hippocampus and neocortex. Kv1.1 potassium channels have been shown to play a role in epilepsy based on recent cloning experiments where deletion of the Kv1.1 potassium channel in mice causes epilepsy (Smart, S. L., et al., Neuron, 1998, 20, 809). In vitro, tissue manipulations using material from these animals which only marginally increase excitability in normal tissue (e.g., raising extracellular potassium or treatment with the GABAA antagonist bicuculine) result in synchronous burst discharges and long-lasting depolarizations in hippocampal CA3 pyramidal neurons. Furthermore, mutations in human genes thought to correspond to Kv1.1 result in hyperexcitable phenotypes, including cases of episodic ataxia and myokymia (Browne, D. L., et al., Nat. Genet., 1994, 8, 136) as well as benign neonatal convulsions, an autosomal dominant form of early-onset epilepsy (Biervert, C., et al., Science, 1998, 279, 403; Charlier, C., et al., Nat. Genet., 1998, 18, 53; Singh, N. A., et al., Nat. Genet., 1998, 18, 25). Additionally, reports of epilepsy in family members affected by the Kv1.1 mutation and diagnosed with episodic ataxia and myokymia have appeared (Zuberi, S. M., et al., Epilepsia, 1997, 38 (supp. 3), 104; Zuberi, S. M., et al., Brain, 1999, 122, 817), correlating the Kv1.1 gene mutation with epilepsy.
Thus, the available evidence suggests that a decrease in Kv1.1 function may act as a mitigating factor in neuronal hyperexcitable disease states, such as epilepsy. Other disease states or conditions affected by neuronal hyperexcitability include for example episodic ataxia, myokymia, neonatalconvulsions, cerebral ischemia, cerebral palsy, stroke, traumatic brain injury, traumatic spinal cord injury, asphyxia, anoxia or prolonged cardiac surgery.
It has also been shown that potassium ion channel openers also play a role in the release and/or regulation of glutamate in mammals (Zini, S. et al., Neuroscience Letters, 1993, 153:202–205). Thus, it is believed compounds that inhibit the inactivation of Kv1.1 will be useful for treating conditions associated with the abnormal release of glutamate including for example hypoglycemia or diseases associated with glutamate release such as Parkinson's disease, Huntingdon's disease, Alzheimer's disease, amyotrophic lateral sclerosis, or AIDS related dementia or combinations thereof.
Thus it would be desirable to find agents that activate Kv1.1 currents or inhibit the inactivation of Kv1.1 currents in mammals. Moreover, as it has been shown that Kv1.1 α-subunits associate and co-localize with Kvβ1 in seizure-sensitive brain regions (Rhodes, K. J., et al., J. Neurosci., 1997, 17, 8246), it would be desirable to find agents that activate or inhibit the inactivation of Kv1.1 potassium channel currents that are associated with Kvβ1.